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PLoS One. 2017 May 10;12(5):e0177188. doi: 10.1371/journal.pone.0177188. eCollection 2017.

BMP-7 induces apoptosis in human germinal center B cells and is influenced by TGF-β receptor type I ALK5.

Author information

1
Department of Cancer Immunology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo, Norway.
2
Center for Cancer Biomedicine, University of Oslo, Oslo, Norway.
3
Faculty of Medicine, University of Oslo, Oslo, Norway.
4
Laboratory of Cellular Immunology, Ochsner Clinic Foundation, New Orleans, Louisiana, United States of America.
5
Transplantation Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
6
Department of Cellular Therapy, the Norwegian Radium Hospital, Oslo, Norway.

Abstract

Selection and maturation of B cells into plasma cells producing high-affinity antibodies occur in germinal centers (GC). GCs form transiently in secondary lymphoid organs upon antigen challenge, and the GC reaction is a highly regulated process. TGF-β is a potent negative regulator, but the influence of other family members including bone morphogenetic proteins (BMPs) is less known. Studies of human peripheral blood B lymphocytes showed that BMP-6 suppressed plasmablast differentiation, whereas BMP-7 induced apoptosis. Here, we show that human naïve and GC B cells had a strikingly different receptor expression pattern. GC B cells expressed high levels of BMP type I receptor but low levels of type II receptors, whereas naïve B cells had the opposite pattern. Furthermore, GC B cells had elevated levels of downstream signaling components SMAD1 and SMAD5, but reduced levels of the inhibitory SMAD7. Functional assays of GC B cells revealed that BMP-7 suppressed the viability-promoting effect of CD40L and IL-21, but had no effect on CD40L- and IL-21-induced differentiation into plasmablasts. BMP-7-induced apoptosis was counteracted by a selective TGF-β type I receptor (ALK4/5/7) inhibitor, but not by a selective BMP receptor type I inhibitor. Furthermore, overexpression of truncated ALK5 in a B-cell line counteracted BMP-7-induced apoptosis, whereas overexpression of truncated ALK4 had no effect. BMP-7 mRNA and protein was readily detected in tonsillar B cells, indicating a physiological relevance of the study. Altogether, we identified BMP-7 as a negative regulator of GC B-cell survival. The effect was counteracted by truncated ALK5, suggesting greater complexity in regulating BMP-7 signaling than previously believed.

PMID:
28489883
PMCID:
PMC5425193
DOI:
10.1371/journal.pone.0177188
[Indexed for MEDLINE]
Free PMC Article

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